This collaborative proposal responds to RFA HL-98-003 and has Imaging, Biomechanics and Vascular Biology components. This combined submission seeks to identify imaging, hemodynamic, elastomechanical and pathobiologic parameters that distinguish the vulnerable atherosclerotic plaque. The imaging component will develop and validate MR angiographic methods that yield high resolution 3D measurements of the carotid bifurcation in patients about to undergo endarterectomy. Plaque lumenal contour and composition will be validated by ex vivo MR imaging and histologic studies. The lumenal contour information will be used by the Biomechanics group to develop advanced computational fluid dynamics codes, verified by experimental flow models, that predict regional variations in wall shear stress within the deceased artery. Some excised plaques will also be subjected to analysis using nanoindentation to determine the elastomechanical properties of various regions of the plaque including the fibrous cap; these studies will also be correlated with histology. The Vascular Biology group will focus on how shear stress regulates the expression of matrix metalloproteinases by endothelial cells and platelets. In vitro studies using a cone-plate viscometer will study the shear-induced cellular and molecular biologic mechanisms that regulate expression of the metalloproteinases. Analysis by immunohistochemistry and in situ hybridization will be coupled with quantitative densitometry to measure regional differences in metalloproteinase expression within excised plaques. These results will be correlated with the wall shear stress and elastomechanical predications in order to determine the degree to which metalloproteinase expression in plaques may be regulated by biomechanical forces.